A new class of hexa-peptide opioid antagonists, termed acetalins, have been identified. They exhibit potent binding activity at mu specific opioid receptors, with approximately a 10-fold lower activity at delta, and greater than 100-fold less binding activity at kappa-1 and kappa-2 receptors. They have been found to be potent mu receptor antagonists in the guinea pig ileum assay, and relatively weak delta antagonists in the mouse vas deferens assay. In order to increase the mu receptor specificity, the proposed study will involve the synthesis of 240 single position analogs of the most potent L- and D-amino acid acetalins (Ac- RFMWMR-NH2 and Ac-rfwink-NH2, respectively). The goal is to develop a highly mu specific receptor antagonist which is not broken down by proteolytic enzymes. The most specific mu antagonists will be tested for their ability to antagonize the intestinal immobility caused by chronic morphine treatment. The long term goal is to be able to block the deleterious effects of intestinal immobility (constipation) in patients requiring long term morphine treatment.